Updated results from the ORIENT-11 trial showed that adding sintilimab to chemotherapy significantly prolongs overall survival (OS) in patients with previously untreated, advanced nonsquamous non-small cell lung cancer (NSCLC). These results were published in the Journal of Thoracic Oncology.
The phase 3 ORIENT-11 trial (ClinicalTrials.gov Identifier: NCT03607539) included 397 patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC without sensitizing EGFR or ALK aberrations.
The patients were randomly assigned 2:1 to receive sintilimab plus pemetrexed and platinum chemotherapy (266 patients) or placebo plus pemetrexed and platinum chemotherapy (131 patients). The patients were stratified according to PD-L1 expression levels.
At the interim analysis, the median follow-up for progression-free survival (PFS) was 14.8 months. The median PFS was significantly longer in the combination group than in the placebo group — 9.2 months and 5.0 months, respectively (hazard ratio [HR], 0.49; 95% CI, 0.38-0.63; P <.0001).
The median follow-up for OS was 22.9 months. The median OS was significantly longer in the combination group than in the placebo group — not reached and 16.8 months, respectively (HR, 0.60; 95% CI, 0.45-0.79; P =.0003).
The addition of sintilimab to chemotherapy significantly improved PFS in patients with high immune cell infiltration (HR, 0.31; 95% CI, 0.14-0.71; P =.0057) and medium immune cell infiltration (HR, 0.26; 95% CI; 0.15-0.47; P <.0001).
However, there was no additional benefit in patients with low or absent immune cell infiltration (HR, 0.86; 95% CI, 0.44-1.68; P = .6530). This indicates that chemotherapy could not prime “immune deserts” to obtain benefit from inhibition of PD-1, according to the researchers.
Results also showed that, in the combination group, patients with high major histocompatibility complex (MHC) class II-related gene expression had significantly longer PFS than those with low MHC class II-related gene expression (HR, 0.32; 95% CI, 0.19-0.54; P <.0001). Patients with high MHC class I-related gene expression also had longer PFS (HR, 0.54; 95% CI, 0.33-0.90; P =.0183).
However, in the chemotherapy group, the PFS was comparable between patients with high and low MHC class II-related gene expression (HR, 0.79; 95% CI, 0.45-1.37; P =.3950) and those with high and low MHC class I-related gene expression (HR, 1.24; 95% CI, 0.71-2.16; P =.4540).
Only MHC class II-related gene expression was significantly associated with OS in the combination group. Patients with high MHC class II-related gene expression had significantly longer OS (HR, 0.36; 95% CI, 0.20-0.64; P =.0005) compared with patients who had low MHC class II-related gene expression.
The researchers noted that patients with low or negative PD-L1 expression could still benefit from the combination treatment if their MHC class II expression was high. As compared with MHC class II, MHC class I was found to be “less relevant” in the combination setting.
“Collectively, these findings suggest that antigen presentation, particularly MHC class II pathway, is critical to gain clinical benefit from immune-combination treatment,” the researchers wrote. “These results might shed light into the mode of action of this combination therapy and highlight the potential value of MHC class II expression to select patients for immune-combination treatment.”
Disclosures: This research was partially supported by Innovent Biologics, Inc. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
Yang Y, Sun J, Wang Z, et al. Updated overall survival data and predictive biomarkers of sintilimab plus pemetrexed and platinum as first-line treatment for locally advanced or metastatic nonsquamous NSCLC in the phase 3 ORIENT-11 study. J Thorac Oncol. Published online August 3, 2021. doi:10.1016/j.jtho.2021.07.015